The present invention relates to a pharmaceutical composition for use as an NPY Y5 receptor antagonist, specifically, anti-obestic agent and novel compounds having an anti-obestic activity.
Neuropeptide Y (hereinafter referred to as NPY) is a peptide which consists of 36 amino acid residues and was isolated from porcine brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals.
It has been reported that NPY possesses a stimulating activity of food intake, an anti-seizure activity, a learning-promoting activity, an anti-anxiety activity, an anti-stress activity etc. in central nervous system, and it may be pivotally involved in the central nervous system diseases such as depression, Alzheimer""s disease and Parkinson""s disease. NPY is thought to be associated with the cardiovascular diseases, since it induces a contraction of smooth muscles such as blood vessels or cardiac muscles in the peripheral tissues. Furthermore, NPY is also known to be involved in the metabolic diseases such as obesity, diabetes, and hormone abnormalities (Trends in Pharmacological Sciences, Vol.15, and 153 (1994)). Therefore, an NPY receptor antagonist is expected as a medicine for preventing or treating various diseases involved in the NPY receptor.
Subtypes of Y1, Y2, Y3, Y4, Y5, and Y6 have now been identified as the NPY receptor (Trends in Pharmacological Sciences, Vol.18, and 372 (1997)). It has been suggested that the Y5 receptor is at least involved in the feeding behavior and its antagonist is expected as an anti-obestic agent (Peptides, Vol.18, and 445 (1997)).
Quinazoline compounds having similar structures to those of the compounds of the present invention and exhibiting an NPY receptor antagonistic activity are described in WO97/20820, WO97/20821, WO97/20823 and the like. In addition, it is described that urea derivatives having a sulfonamide group and amide derivatives having a sulfonyl group in WO 99/64349 and benzyl sulfonamide derivatives in EP1010691-A, have an NPY antagonistic activity.
Compounds having similar structures to those of the compounds of the present invention are described in JP59-16871-A and WO97/15567. Their activities are quite different from that of the present invention and these documents do not suggest the present invention.
The object of the present invention is to provide a superior pharmaceutical composition for use as an NPY Y5 receptor antagonist and novel compounds having the activity.
The present invention provides
[1] A pharmaceutical composition for use as an NPY Y5 receptor antagonist comprising a compound of the formula (I): 
wherein R1 is optionally substituted lower alkyl, optionally substituted cycloalkyl or optionally substituted aryl,
R2 is hydrogen or lower alkyl, and R1 and R2 taken together may form lower alkylene,
n is 1 or 2,
X is optionally substituted lower alkylene,
optionally substituted lower alkenylene,
optionally substituted xe2x80x94CO-lower alkylene,
optionally substituted xe2x80x94CO-lower alkenylene or 
wherein R3, R4, R5and R6 are each independently hydrogen or lower alkyl, 
is optionally substituted cycloalkylene, optionally substituted cycloalkenylene, optionally substituted bicycloalkylene, optionally substituted arylene or optionally substituted heterocyclediyl and p and q are each independently 0 or 1,
xe2x80x94NR2xe2x80x94Xxe2x80x94 may be 
xe2x80x83wherein 
is piperidinediyl, piperazinediyl, pyridinediyl, pyrazinediyl, pyrrolidinediyl or pyrrolediyl and U is single bond, lower alkylene or lower alkenylene,
Y is OCONR7, CONR7, CSNR7, NR7CO or NR7CS,
R7 is hydrogen or lower alkyl, and
Z is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted amino, optionally substituted lower alkoxy, optionally substituted carbocyclyle or optionally substituted heterocyclyl,
prodrug, pharmaceutically acceptable salt or solvate thereof,
[2] The pharmaceutical composition for use as an NPY Y5 receptor antagonist described in [1] wherein R2 is hydrogen or lower alkyl and Z is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted carbocyclyl, optionally substituted heterocyclyl or optionally substituted amino, provided that R1 is optionally substituted C3 to C10 alkyl when Z is optionally substituted amino,
[3] The pharmaceutical composition for use as an NPY Y5 receptor antagonist described in [1] wherein R1 is optionally substituted lower alkyl or optionally substituted cycloalkyl, X is optionally substituted lower alkylene, optionally substituted lower alkenylene or 
wherein 
is the same as defined in [1], and Z is optionally substituted lower alkyl, optionally substituted carbocyclyl or optionally substituted heterocyclyl,
[4] The pharmaceutical composition for use as an NPY Y5 receptor antagonist described in any one of [1] to [3] wherein R1 is optionally substituted C3 to C10 alkyl,
[5] The pharmaceutical composition for use as an NPY Y5 receptor antagonist described in any one of [1] to [4] which is an anti-obestic agent,
[6] The pharmaceutical composition for use as an NPY Y5 receptor antagonist described in any one of [1] to [4] which is an anorectic agent,
[7] A method for treating and/or preventing obesity comprising administering an effective dose of an NPY Y5 receptor antagonist described in any one of [1] to [4],
[8] A method for suppressing food intake comprising administering an effective dose of an NPY Y5 receptor antagonist described in any one of [1] to [4],
[9] Use of an NPY Y5 receptor antagonist described in any one of [1] to [4] for manufacturing a medicine for treating and/or preventing obesity,
[10] Use of an NPY Y5 receptor antagonist described in any one of [1] to [4] for manufacturing a medicine for suppressing food intake,
[11] A compound of the formula (I): 
wherein X is C2 to C6 alkylene or C3 to C6 alkenylene, R1 is optionally substituted C3 to C10 alkyl or optionally substituted C5 to C6 cycloalkyl and the other symbols are the same as defined in [1], provided that Z is not lower alkylphenylamino,
hydroxy(lower)alkylphenylamino and acylphenylamino when Y is NR7CO,
prodrug, pharmaceutically acceptable salt or solvate thereof,
[12] The compound described in [11] wherein Z is optionally substituted lower alkyl or optionally substituted phenyl, prodrug, pharmaceutically acceptable salt or solvate thereof,
[13] A compound of the formula (I): 
wherein X is 
is optionally substituted cycloalkylene, optionally substituted cycloalkenylene, optionally substituted bicycloalkylene or optionally substituted piperidinylene, R1 is optionally substituted C3 to C10 alkyl or optionally substituted C5 to C6 cycloalkyl and the other symbols are the same as defined in [1], prodrug, pharmaceutically acceptable salt or solvate thereof,
[14] The compound described in [13] wherein is optionally substituted cyclohexylene or optionally substituted piperidinylene and p and q are simultaneously 0, prodrug, pharmaceutically acceptable salt or solvate thereof,
[15] The compound described in [13] or [14] wherein Y is CONH, prodrug, pharmaceutically acceptable salt or solvate thereof,
[16] The compound described in any one of [13] to [15] wherein Z is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted pyridyl or optionally substituted benzopyranyl, prodrug, pharmaceutically acceptable salt or solvate thereof,
[17] A compound of the formula (I): 
wherein X is 
R1 is optionally substituted C3 to C10 alkyl or optionally substituted C5 to C6 cycloalkyl,
Z is p-(lower)alkylphenyl and the other symbols are the same as defined in [1], provided that Z is not p-n-butylphenyl when R1 is isopropyl,
prodrug, pharmaceutically acceptable salt or solvate thereof,
[18] A compound of the formula (I): 
wherein X is 
is heteroarylene, R1 is optionally substituted C3 to C10 alkyl or optionally substituted C5 to C6 cycloalkyl and the other symbols are the same as defined in [1], prodrug, pharmaceutically acceptable salt or solvate thereof,
[19] The compound described in [18] wherein 
is thiophenediyl or furandiyl, prodrug, pharmaceutically acceptable salt or solvate thereof and
[20] A pharmaceutical composition comprising the compound described in any one of [11] to [19], prodrug, pharmaceutically acceptable salt or solvate thereof.
In the present specification, the term xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine, bromine and iodine. Fluorine or chlorine is preferable.
The term xe2x80x9cprotective groupxe2x80x9d in xe2x80x9coptionally protected hydroxyxe2x80x9d and xe2x80x9coptionally protected hydroxy(lower)alkylxe2x80x9d includes all of hydroxy protecting groups usually used. For example, acyl such as acetyl, trichloroacetyl and benzoyl, lower alkoxycarbonyl such as t-butoxycarbonyl, lower alkylsulfonyl such as methane sulfonyl, lower alkoxy(lower)alkyl such as methoxymethyl, trialkylsilyl such as t-butyldimethylsilyl are included.
The term xe2x80x9clower alkylxe2x80x9d includes C1 to C10 straight or branched alkyl. The examples of xe2x80x9clower alkylxe2x80x9d are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl.
xe2x80x9cLower alkylxe2x80x9d represented by R1 is preferably C3 to C10 alkyl, more preferably C3 to C6 alkyl and most preferably isopropyl or t-butyl.
xe2x80x9cLower alkylxe2x80x9d in other cases is preferably C1 to C6 alkyl and more preferably C1 to C4 alkyl.
The examples of substituents of xe2x80x9coptionally substituted lower alkylxe2x80x9d represented by Z are, (1) halogen; (2) cyano;
(3) the following groups (i) to (xvi), which are optionally substituted with one or more substituents selected from xe2x80x9ca substituents group xcex2xe2x80x9d defined below,
(i) hydroxy, (ii) lower alkoxy, (iii) mercapto, (iv) lower alkylthio, (v) acyl, (vi) acyloxy, (vii) carboxy, (viii) lower alkoxycarbonyl, (ix) imino, (x) carbamoyl, (xi) thiocarbamoyl, (xii) lower alkylcarbamoyl, (xiii) lower alkylthiocarbamoyl, (xiv) amino, (xv) lower alkylamino or (xvi) heterocyclylcarbonyl; or
(4) a group of the formula: 
wherein R10 and R11 are each independently hydrogen or lower alkyl and when this group has two or more of R10 and/or two or more of R11, each R10 and/or each R11 may be different,
W is single bond, O, S or NR12,
R12 is hydrogen, lower alkyl or phenyl, 
is cycloalkyl, bicycloalkyl, cycloalkenyl, aryl or heterocyclyl, each of which is optionally substituted with one or more of substituents selected from xe2x80x9ca substituents group xcex1xe2x80x9d defined below and
s is an integer of 0 to 4.
In the present specification, xe2x80x9ca substituents group xcex1xe2x80x9d is a group constituting of (1) halogen; (2) oxo; (3) cyano; (4) nitro; (5) imino optionally substituted with lower alkyl or hydroxy;
(6) the following groups (i) to (xxi), which are optionally substituted with one or more of groups selected from the substituents group A,
(i) hydroxy, (ii) lower alkyl, (iii) lower alkenyl, (iv) lower alkoxy, (v) carboxy, (vi) lower alkoxycarbonyl, (vii) acyl, (viii) acyloxy, (ix) imino, (x) mercapto, (xi) lower alkylthio, (xii) carbamoyl, (xiii) lower alkylcarbamoyl, (xiv) cycloalkylcarbamoyl, (xv) thiocarbamoyl, (xvi) lower alkylthiocarbamoyl, (xvii) lower alkylsulfinyl, (xviii) lower alkylsulfonyl, (xix) sulfamoyl, (xx) lower alkylsulfamoyl and (xxi) cycloalkylsulfamoyl;
(7) the following groups (i) to (v), which are optionally substituted with the substituents group xcex2, lower alkyl, lower alkoxy(lower)alkyl, optionally protected hydroxy(lower)alkyl, halogeno(lower)alkyl, lower alkylsulfonyl and/or arylsulfonyl,
(i) cycloalkyl, (ii) cycloalkenyl, (iii) cycloalkyloxy, (iv) amino and (v) alkylenedioxy; and
(8) the following groups (i) to (xii), which are optionally substituted with the substituents group xcex2, lower alkyl, halogeno(lower)alkyl and/or oxo,
(i) phenyl, (ii) naphthyl, (iii) phenoxy, (iv) phenyl(lower)alkoxy, (v) phenylthio, (vi) phenyl(lower)alkylthio, (vii) phenylazo, (viii) heterocyclyl, (ix) heterocyclyloxy, (x) heterocyclylthio, (xi) heterocyclylcarbonyl and (xii) heterocyclylsulfonyl.
The preferable examples of the substituents group xcex1 as substituents for B ring are halogen; nitro; hydroxy;
optionally substituted lower alkyl wherein the substituents is halogen, cyano, phenyl, carboxy and/or lower alkoxycarbonyl;
lower alkenyl; lower alkoxycarbonyl(lower)alkenyl;
optionally substituted lower alkoxy wherein the substituents is halogen, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkylamino and/or cyano;
acyl; hydroxyimino; lower alkylthio; lower alkylsulfinyl; sulfamoyl;
optionally substituted amino wherein the substituents is lower alkyl, optionally protected hydroxy(lower)alkyl, phenyl and/or acyl;
alkylenedioxy; cyanophenyl; heterocyclylphenyl; biphenylyl; phenoxy; phenylazo optionally substituted with lower alkyl; or
optionally substituted heterocyclyl wherein the substituents is optionally protected hydroxy, mercapto, halogen, lower alkyl, cycloalkyl, lower alkoxycarbonyl, amino, lower alkoxycarbonyl amino, carbamoyl, oxo, phenyl, lower alkoxyphenyl or heterocyclyl. More preferable examples are halogen; lower alkyl optionally substituted with halogen; or lower alkoxy optionally substituted with halogen.
xe2x80x9cA substituents group xcex2xe2x80x9d is a group consisting of halogen, optionally protected hydroxy, mercapto, lower alkoxy, lower alkenyl, amino, lower alkylamino, lower alkoxycarbonylamino, lower alkylthio, acyl, carboxy, lower alkoxycarbonyl, carbamoyl, cyano, cycloalkyl, phenyl, phenoxy, lower alkylphenyl, lower alkoxyphenyl, halogenophenyl, naphthyl and heterocyclyl.
Examples of the substituents for xe2x80x9coptionally substituted lower alkylxe2x80x9d represented by any other than Z (e.g., R1) are one or more substituents selected from the substituents group xcex2. The lower alkyl may be substituted with these substituents at any possible positions.
The lower alkyl part in xe2x80x9clower alkoxyxe2x80x9d, xe2x80x9clower alkoxycarbonylxe2x80x9d, xe2x80x9clower alkoxycarbonyl(lower)alkylxe2x80x9d, xe2x80x9clower alkylphenylxe2x80x9d, xe2x80x9clower alkoxyphenylxe2x80x9d, xe2x80x9clower alkylcarbamoylxe2x80x9d, xe2x80x9clower alkylthiocarbamoylxe2x80x9d, xe2x80x9clower alkylaminoxe2x80x9d, xe2x80x9chalogeno(lower)alkylxe2x80x9d, xe2x80x9chydroxy(lower)alkylxe2x80x9d, xe2x80x9cphenyl(lower)alkoxyxe2x80x9d, xe2x80x9clower alkylthioxe2x80x9d, xe2x80x9cphenyl(lower)alkylthioxe2x80x9d, xe2x80x9clower alkoxycarbonylaminoxe2x80x9d, xe2x80x9clower alkoxycarbonyl(lower)alkenylxe2x80x9d, xe2x80x9clower alkylsulfinylxe2x80x9d, xe2x80x9clower alkylsulfonylxe2x80x9d, xe2x80x9caryl(lower)alkoxycarbonylxe2x80x9d, xe2x80x9clower alkylbenzoylxe2x80x9d and xe2x80x9clower alkoxybenzoylxe2x80x9d is the same as defined in the above xe2x80x9clower alkylxe2x80x9d.
Examples of substituents for xe2x80x9coptionally substituted lower alkoxyxe2x80x9d are one or more substituents selected from the substituents group xcex2. Preferable examples are phenyl, lower alkylphenyl, lower alkoxyphenyl, naphthyl and heterocyclyl.
The term xe2x80x9ccycloalkylxe2x80x9d includes C3 to C8 cyclic alkyl and preferably C5 to C6 cyclic alkyl. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Examples of substituents for xe2x80x9coptionally substituted cycloalkylxe2x80x9d are one or more substituents selected from the substituents group xcex1 and the cycloalkyl may be substituted with these substituents at any possible positions.
The term xe2x80x9cbicycloalkylxe2x80x9d includes a group which is formed by excluding one hydrogen from a C5 to C8 aliphatic cycle containing two rings which possess two or more of atoms in common. Examples are bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and bicyclo[3.2.1]octyl.
The term xe2x80x9clower alkenylxe2x80x9d includes C2 to C10, preferably C2 to C8 and more preferably C3 to C6 straight or branched alkenyl having one or more double bonds at any possible positions. Examples are vinyl, propenyl, isopropenyl, butenyl, isobutenyl, phenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl and decenyl.
The xe2x80x9clower alkenylxe2x80x9d part in xe2x80x9clower alkoxycarbonyl(lower)alkenylxe2x80x9d is the same as the above xe2x80x9clower alkenylxe2x80x9d.
Examples of the substituents for xe2x80x9coptionally substituted lower alkenylxe2x80x9d are halogen, lower alkoxy, lower alkenyl, amino, lower alkylamino, lower alkoxycarbonylamino, lower alkylthio, acyl, carboxy, lower alkoxycarbonyl, carbamoyl, cyano, cycloalkyl, phenyl, lower alkylphenyl, lower alkoxyphenyl, naphthyl and/or heterocyclyl.
The term xe2x80x9cacylxe2x80x9d includes (1) C1 to C10, preferably C1 to C6 and more preferably C1 to C4 straight or branched alkylcarbonyl or alkenylcarbonyl, (2) C4 to C9 and preferably C4 to C7 cycloalkylcarbonyl and (3) C7 to C11 arylcarbonyl. Examples are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.
The xe2x80x9cacylxe2x80x9d part in xe2x80x9cacyloxyxe2x80x9d is the same as the above.
The term xe2x80x9ccycloalkenylxe2x80x9d includes a group having at least one double bond at any possible positions in the above cycloalkyl. Examples are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cyclohexadienyl.
Examples of substituents for xe2x80x9coptionally substituted cycloalkenylxe2x80x9d are one or more substituents selected from the substituents group xcex2.
Examples of substituents for xe2x80x9coptionally substituted aminoxe2x80x9d are the substituents group xcex2, optionally substituted benzoyl and/or optionally substituted heterocyclylcarbonyl wherein the substituents is hydroxy, lower alkyl, lower alkoxy and/or lower alkylthio.
The term xe2x80x9carylxe2x80x9d includes a monocyclic of polycyclic aromatic carbocyclyl group and examples are phenyl, naphthyl, anthryl and phenanthryl. xe2x80x9cArylxe2x80x9d includes aryl fused with other a non-aromatic carbocyclyl group, for example, indanyl, indenyl, biphenylyl, acenaphthyl, tetrahydronaphthyl and fluorenyl. Phenyl is preferable.
The aryl part in xe2x80x9caryl lower alkoxycarbonylxe2x80x9d is the same as the above.
The term xe2x80x9coptionally substituted arylxe2x80x9d and xe2x80x9coptionally substituted phenylxe2x80x9d represented by Z include the above xe2x80x9carylxe2x80x9d and xe2x80x9cphenylxe2x80x9d respectively, which may be substituted with the substituents group xcex1 or lower alkyl which may be substituted with one or more group selected from the substituents group xcex1.
Examples of the substituents for xe2x80x9coptionally substituted arylxe2x80x9d and xe2x80x9coptionally substituted phenylxe2x80x9d represented by any other than Z are one or more groups selected from the substituents group xcex2.
The term xe2x80x9ccarbocyclylxe2x80x9d includes the above xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9ccycloalkenylxe2x80x9d, xe2x80x9cbicycloalkylxe2x80x9d and xe2x80x9carylxe2x80x9d.
The term xe2x80x9cnon-aromatic carbocyclylxe2x80x9d includes the above xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9ccycloalkenylxe2x80x9d and xe2x80x9cbicycloalkylxe2x80x9d.
The term xe2x80x9coptionally substituted carbocyclylxe2x80x9d includes the above xe2x80x9coptionally substituted cycloalkylxe2x80x9d, xe2x80x9coptionally substituted cycloalkenylxe2x80x9d, xe2x80x9coptionally substituted bicycloalkylxe2x80x9d and xe2x80x9coptionally substituted arylxe2x80x9d.
The term xe2x80x9cheterocyclylxe2x80x9d includes a heterocyclic group containing at least one heteroatom arbitrarily selected from O, S and N. For example, 5- or 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl; fused heterocyclyl consisting of two rings such as indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl benbzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazoropyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthyridinyl, dihydropyridyl, tetrahydroquinolyl and tetrahydrobenzothienyl; fused heterocyclyl consisting of three rings such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl and dibenzofuryl; and non-aromatic heterocyclyl such as dioxanyl, thiiranyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl and tetrahydroisothiazolyl.
xe2x80x9cFused heterocyclylxe2x80x9d fused with a ring other than a heterocycle (e.g., benzothiazolyl), may connect at any possible position.
Substituents for xe2x80x9coptionally substituted heterocyclylxe2x80x9d are the same as those for the above xe2x80x9coptionally substituted arylxe2x80x9d.
Heterocyclyl parts in xe2x80x9cheterocyclylcarbonylxe2x80x9d, xe2x80x9cheterocyclyloxyxe2x80x9d, xe2x80x9cheterocyclylthioxe2x80x9d and xe2x80x9cheterocyclyl substituted phenylxe2x80x9d are the same as the above xe2x80x9cheterocyclylxe2x80x9d.
The term xe2x80x9clower alkylenexe2x80x9d includes a bivalent group comprising 1 to 6 of methylene, preferably 2 to 6 of methylene and more preferably 3 to 6 of methylene. For example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene are included. Tetramethylene is preferable.
xe2x80x9cR1 and R2 taken together may form lower alkylenexe2x80x9d includes the case 
Preferable examples are 
Lower alkylene part in xe2x80x9clower alkylenedioxyxe2x80x9d is the same as the above xe2x80x9clower alkylenexe2x80x9d. Methylenedioxy or ethylenedioxy is preferable.
The term xe2x80x9clower alkenylenexe2x80x9d includes a bivalent group comprising 2 to 6 of methylene, preferably 3 to 6 of methylene and more preferably 4 to 5 of methylene and including at least one double bond.
The term xe2x80x9ccycloalkylenexe2x80x9d includes a bivalent group which is formed by excluding one hydrogen from the above xe2x80x9ccycloalkylxe2x80x9d. A preferable example of cycloalkylene represented by X is 1,4-cyclohexanediyl.
The term xe2x80x9ccycloalkenylenexe2x80x9d includes a group containing at least one double bonds in the above cycloalkylene.
The term xe2x80x9cbicycloalkylenexe2x80x9d includes a group which is formed by excluding one hydrogen from the above xe2x80x9cbicycloalkylxe2x80x9d. Examples are bicyclo[2.1.0]pentylene, bicyclo[2.2.1]heptylene, bicyclo[2.2.2]octylene, and bicyclo[3.2.1]octylene.
The term xe2x80x9cheterocyclediylxe2x80x9d includes a bivalent group which is formed by excluding one hydrogen from the above xe2x80x9cheterocyclylxe2x80x9d. Piperidinediyl, piperazinediyl, pyridinediyl, pyrimidinediyl, pyrazinediyl, pyrrolidinediyl or pyrrolediyl is preferable and piperidindiyl is more preferable.
The term xe2x80x9carylenexe2x80x9d includes a bivalent group which is formed by excluding one hydrogen from the above xe2x80x9carylxe2x80x9d. Phenylene is preferable.
The term xe2x80x9cheteroarylenexe2x80x9d includes aromatic groups in the above xe2x80x9cheterocyclediylxe2x80x9d. Examples are pyrrolediyl, imidazolediyl, pyrazolediyl, pyridinediyl, pyridazinediyl, pyrimidinediyl, pyrazinediyl, triazolediyl, triazinediyl, isoxazolediyl, oxazolediyl, oxadiazolediyl, isothiazolediyl, thiazolediyl, thiadiazolediyl, furandiyl and thiophenediyl.
One or more groups selected from the substituents group xcex2 are examples of substituents for xe2x80x9coptionally substituted lower alkylenexe2x80x9d, xe2x80x9coptionally substituted lower alkenylenexe2x80x9d, xe2x80x9coptionally substituted cycloalkylenexe2x80x9d, xe2x80x9coptionally substituted cyclohexylenexe2x80x9d, xe2x80x9coptionally substituted bicycloalkylenexe2x80x9d, xe2x80x9coptionally substituted cycloalkenylenexe2x80x9d, xe2x80x9coptionally substituted phenylenexe2x80x9d, xe2x80x9coptionally substituted heterocyclediylxe2x80x9d and xe2x80x9coptionally substituted piperidinylenexe2x80x9d. Halogen, hydroxy, lower alkyl, halogeno(lower)alkyl, lower alkoxy, amino, lower alkylamino, acyl, carboxy or lower alkoxycarbonyl is preferable. These substituents may attach to any possible positions.
When xe2x80x94NR2xe2x80x94Xxe2x80x94 is 
U is preferably single bond or methylene. More preferably, 
is 
The compounds of the present invention include any formable and pharmaceutically acceptable salts thereof. Examples of xe2x80x9cthe pharmaceutically acceptable saltxe2x80x9d are salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; salts with organic acids such as para-toluenesulfonic acid, methanesulfonic acid, oxalic acid and citric acid; salts with organic bases such as ammonium, trimethylammonium and triethylammonium; salts with alkaline metals such as sodium and potassium; and salts with alkaline earth metals such as calcium and magnesium.
The compounds of the present invention include solvates thereof. Hydrate is preferable and arbitrary numbers of water molecules may coordinate to the compound of the present invention.
The compounds of the present invention include prodrugs thereof. Prodrug includes derivatives of the compounds of the present invention which have a chemically or metabolically decomposable group and can be converted into pharmaceutically active compounds of the present invention in vivo by solvolysis or under the physiological conditions. The methods for selecting and producing suitable prodrugs are described in Design of Prodrugs, Elsevier, Amsterdam 1985.
When a compound (I) of the present invention has carboxy, examples of prodrugs are an ester derivative and an amide derivative, which can be produced by reacting a compound (I) having carboxy with a suitable alcohol or a suitable amine, respectively.
When a compound (I) of the present invention has hydroxy, an example of prodrugs is an acyloxy derivative, which can be synthesized by reacting a compound (I) having hydroxy with a suitable acyl halide or a suitable acid anhydride.
When a compound (I) of the present invention has amino, an example of prodrugs is an amide derivative, which can be synthesized by reacting a compound (I) having amino with a suitable acid halide or a suitable mixed acid anhydride.
When the compound (I) of the present invention has an asymmetric carbon atom, it includes racemates, all of enantiomers and all of stereoisomers such as diastereomer, epimer and enantiomer thereof.
When the compound (I) of the present invention having one or more double bonds forms an E isomer or Z isomer, the compound (I) includes both isomers. When X is cycloalkylene, the compound (I) includes both of cis isomer and trans isomer.
For example, the compound (I) of the present invention can be synthesized by the following methods.
(Compounds Wherein Y=CONR7) 
wherein Hal is halogen, Q is an amino protecting group and the other symbols are the same as the above.
Step A
Compound 1 is reacted with Amino Compound 2 having the desired substituent Z and R7 in a suitable solvent at 0xc2x0 C. to 50xc2x0 C. for several minutes to several hours. As solvents, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, water, a mixture thereof etc. can be used. An activator such as thionyl chloride, acid halide, acid anhydride and activated ester can be used, if necessary.
Step B
Compound 3 is deprotected by the usual method and reacted with Sulfonyl Halide 4 having the desired substituent R1 in a suitable solvent at 0xc2x0 C. to 50xc2x0 C. for several minutes to several hours to give Compound (I-A) wherein n is 2. Tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, water and the mixture thereof etc. can be used as a solvent.
Step C
Compound (I-B) wherein n is 1 can be synthesized by reacting Compound 3 with Sulfinyl Halide 5 having substituent R1. The conditions for the reaction are the same as those of the above Step B.
Step D
Compound (I-B) obtained in Step C is oxidized by the usual method to give Compound (I-A) wherein n is 2. m-Chloroperbenzoic acid, peracetic acid, hydrogen peroxide, trifluoroperacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate etc. can be used as an oxidizer and the reaction may be carried out at 0xc2x0 C. to 50xc2x0 C. Examples of solvents are tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, water, methanol, ethanol, isopropanol and mixture thereof.
In case X is heterocyclediyl containing at least one N atom and the N atom connects to CONR7xe2x80x94Z in the compound (I), the following reaction may be employed to obtain Compound (I-Axe2x80x2) or (I-Bxe2x80x2). Step D may be carried out just after Step C or Step E. 
wherein R is lower alkyl or aryl and L is a leaving group.
Step C
Compound 5 is reacted with Compound 6 in a similar manner to the above Step C to give Compound 7.
Step E
Thus obtained Compound 7 is treated with a base in a suitable solvent to give Compound 8. For example, barium hydroxide, sodium hydroxide, potassium hydroxide, hydrazine or lithium propanethiolate can be used as a base. As a solvent, tetrahydrofuran, dimethylformamide, dioxane, acetone, acetonitrile, methanol, ethanol, propanol, water, the mixture thereof or the like can be used. The reaction can be carried out at 0xc2x0 C. to 100xc2x0 C. for several minutes to several tens hours.
Step F
Compound 8 is reacted with Compound 9 having a leaving group and a desired substituent in a suitable solvent in the presence or absence of a base at 0xc2x0 C. to 100xc2x0 C. for several minutes to several days to give Compound (I-Bxe2x80x2). Examples of the leaving group are phenoxy, chloro and trichloromethyl. Examples of the base are triethylamine, pyridine, diisopropylethylamine, sodium hydroxide, potassium carbonate and sodium hydrogencarbonate. Examples of the solvent are tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, methanol, ethanol and the mixture thereof.
Step D
Compound (I-Bxe2x80x2) is reacted in a similar manner to the above Step D to give Compound (I-Axe2x80x2).
(Compound Wherein Y=NR7CO) 
wherein each of the symbols is the same as the above.
Step G and Step B
Compound 10 is reacted with Compound 11 under the same reaction condition as that in Step B. Thus obtained Compound 12 is reacted in a similar manner to the above Step B to give Compound (I-C) wherein n=2.
Step C and Step D
To synthesize Compound (I-D), Compound 12 obtained in Step G may be reacted in similar manners to the above Step C and Step D.
(Compound Wherein Y=OCONR7) 
wherein each of symbols is the same as the above.
Step H
Compound 13 is reacted with Isocianate Compound 14 having a substituent Z in a suitable solvent in the presence or absence of a suitable catalyst at 0xc2x0 C. to 100xc2x0 C. for several minutes to several days to give Compound 15. Examples of the solvent are tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile and the mixture thereof.
Step C and Step D
Thus obtained Compound 15 is reacted in similar manners to Step C and Step D to give Compound (I-E) of the present invention.
(Compound Wherein Y=CSNR7 or NR7CS)
Compound (I) wherein Y is CSNR7 or NR7CS can be synthesized by reacting Compound (I) wherein Y is CONR7 or NR7CO synthesized in any one of the above methods with the Lawesson""s reagent or phosphorus pentasulfide in a suitable solvent at 30xc2x0 C. to 100xc2x0 C. for several minutes to several hours. Examples of the solvent are tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile and the mixture thereof.
Amino groups may be protected with a suitable protecting group in the usual manner at a suitable step. For example, phthalimide, lower alkoxycarbonyl, lower alkenyloxycarbonyl, halogenoalkoxycarbonyl, aryl(lower)alkoxycarbonyl, trialkylsilyl, lower alkylsulfonyl, halogeno(lower)alkylsulfonyl, arylsulfonyl, lower alkylcarbonyl and arylcarbonyl can be used as the protecting group.
After protection of the amino group, the compound is subjected to the above-mentioned reactions and the obtained compound is deprotected by treatment of an acid or a base in a suitable solvent at a suitable stage. Examples of a solvent is tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile and the mixture thereof. Examples of a base are hydrazine, pyridine, sodium hydroxide and potassium hydroxide and examples of an acid are hydrochloric acid, trifluoroacetic acid and hydrofluoric acid.
All of the compounds of the present invention have an NPY Y5 antagonistic activity and the following compounds are specifically preferable.
In the formula (I),
a compound wherein R1 is optionally substituted lower alkyl or optionally substituted cycloalkyl (hereinafter referred to as xe2x80x9cR1 is R1-1xe2x80x9d),
a compound wherein R1 is C3 to C10 alkyl or C5 to C6 cycloalkyl, each of which is optionally substituted with halogen (hereinafter referred to as xe2x80x9cR1 is R1-2xe2x80x9d),
a compound wherein R1 is C3 to C10 alkyl optionally substituted with halogen (hereinafter referred to as xe2x80x9cR1 is R1-3xe2x80x9d),
a compound wherein R1 is isopropyl or t-butyl (hereinafter referred to as xe2x80x9cR1 is R1-4xe2x80x9d),
a compound wherein R2 is hydrogen or C1 to C3 alkyl (hereinafter referred to as xe2x80x9cR2 is R2-1xe2x80x9d),
a compound wherein R2 is hydrogen (hereinafter referred to as xe2x80x9cR2 is R2-2xe2x80x9d),
a compound wherein X is optionally substituted lower alkylene, optionally substituted lower alkenylene or 
xe2x80x83wherein 
is optionally substituted cycloalkylene, optionally substituted cycloalkenylene, optionally substituted bicycloalkylene, optionally substituted phenylene or optionally substituted heterocyclediyl (hereinafter referred to as xe2x80x9cX is X-1xe2x80x9d),
a compound wherein X is C2 to C6 alkylene, C3 to C6 alkenylene or 
xe2x80x83wherein 
is optionally substituted cycloalkylene, optionally substituted cycloalkenylene, optionally substituted bicycloalkylene, optionally substituted phenylene, optionally substituted piperidinylene, optionally substituted thiophenediyl or optionally substituted furandiyl (hereinafter referred to as xe2x80x9cX is X-2xe2x80x9d),
a compound wherein X is C2 to C6 alkylene or 
xe2x80x83wherein is optionally substituted cycloalkylene, optionally substituted phenylene, optionally substituted piperidinylene, optionally substituted thiophenediyl or optionally substituted furandiyl (hereinafter referred to as xe2x80x9cX is X-3xe2x80x9d),
a compound wherein X is (i) C2 to C6 alkylene or (ii) cycloalkylene or phenylene, each of which is optionally substituted with halogen, hydroxy, lower alkyl or halogeno(lower)alkyl (hereinafter referred to as xe2x80x9cX is X-4xe2x80x9d),
a compound wherein X is C2 to C6 alkylene or to C5 to C6 cycloalkylene (hereinafter referred to as xe2x80x9cX is X-5xe2x80x9d),
a compound wherein X is C3 to C6 alkylene or 1,4-cyclohexylene (hereinafter referred to as xe2x80x9cX is X-6xe2x80x9d),
a compound wherein Y is CONR7, CSNR7, NR7CO or NR7CS and R7is hydrogen or C1 to C3 alkyl (hereinafter referred to as xe2x80x9cY is Y-1xe2x80x9d),
a compound wherein Y is CONH, CSNH or NHCO (hereinafter referred to as xe2x80x9cY is Y-2xe2x80x9d),
a compound wherein Y is CONH (hereinafter referred to as xe2x80x9cY is Y-3xe2x80x9d),
a compound wherein Z is optionally substituted lower alkyl, optionally substituted carbocyclyl or optionally substituted heterocyclyl (hereinafter referred to as xe2x80x9cZ is Z-1xe2x80x9d),
a compound wherein Z is xe2x80x94(CR8R9)r-Wxe2x80x94(CR10R11)s-V
wherein R8, R9, R10 and R11 are each independently hydrogen or lower alkyl and when Z has two or more of R8, two or more of R9, two or more of R10 and/or two or more of R11, each of R8, R9, R10 and R11 may be different, W is single bond, O, S or NR12, R12 is hydrogen, lower alkyl or phenyl, V is hydrogen, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, r is an integer of 1 to 4 and s is an integer of 0 to 4
(hereinafter referred to as xe2x80x9cZ is Z-2xe2x80x9d),
a compound wherein Z is xe2x80x94(CH2)r-Wxe2x80x94(CH2)s-V
wherein W is single bond, O, S or NR12, R12 is hydrogen or lower alkyl, V is optionally substituted aryl or optionally substituted heterocyclyl wherein the substituents is halogen, hydroxy, lower alkyl, halogeno(lower)alkyl, lower alkoxy, lower alkenyl, amino, lower alkylamino, acyl, carboxy, lower alkoxycarbonyl, phenyl or monocyclic heteroaryl, r is an integer of 1 to 4 and s is an integer of 0 to 4
(hereinafter referred to as xe2x80x9cZ is Z-3),
a compound wherein Z is xe2x80x94(CH2)r-Wxe2x80x94(CH2)s-V
wherein W is single bond, O, S, NH or NMe, V is optionally substituted phenyl or optionally substituted heteroaryl wherein the substituents is halogen, lower alkyl, halogeno(lower)alkyl, lower alkoxy, amino or lower alkylamino, r is an integer of 1 to 3 and s is an integer of 0 or 1
(hereinafter referred to as xe2x80x9cZ is Z-4xe2x80x9d),
a compound wherein Z is optionally substituted carbocyclyl,
wherein the substituent is halogen; hydroxy;
optionally substituted lower alkyl wherein the substituents is halogen, hydroxy, carboxy, lower alkoxycarbonyl, cyano and/or phenyl;
lower alkenyl optionally substituted with lower alkoxycarbonyl;
optionally substituted lower alkoxy wherein the substituents is halogen, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkylamino, cycloalkyl, cyano and/or heterocyclyl;
cycloalkyl; cycloalkyloxy; acyl; lower alkylthio; carbamoyl; lower alkylcarbamoyl; cycloalkylcarbamoyl; hydroxy imino;
optionally substituted amino wherein the substituents is lower alkyl, optionally protected hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, acyl, lower alkylsulfonyl, arylsulfonyl and/or phenyl;
phenyl optionally substituted with halogen, cyano, phenyl and/or heterocyclyl;
lower alkylsulfinyl; lower alkylsulfamoyl; cycloalkylsulfamoyl;
nitro; cyano; alkylenedioxy; phenylazo optionally substituted with lower alkyl; phenoxy; oxo;
optionally substituted heterocyclyl wherein the substituents is optionally protected hydroxy, mercapto, halogen, lower alkyl, cycloalkyl, lower alkoxycarbonyl, acyl, amino, lower alkoxycarbonylamino, carbamoyl, oxo, phenyl, lower alkoxyphenyl, halogenophenyl, heterocyclyl and/or oxo;
heterocyclylsulfonyl optionally substituted with lower alkyl; heterocyclyloxy; heterocyclylcarbonyl optionally substituted with lower alkyl
(hereinafter referred to as xe2x80x9cZ is Z-5),
a compound wherein Z is optionally substituted phenyl
wherein the substituents is halogen; hydroxy; lower alkyl optionally substituted with halogen, hydroxy, lower alkoxycarbonyl, cyano and/or phenyl; lower alkoxycarbonyl(lower)alkenyl; lower alkoxy optionally substituted with halogen, lower alkoxy, lower alkoxycarbonyl, cycloalkyl and/or heterocyclyl; cycloalkyl; cycloalkyloxy; acyl; lower alkylthio; carbamoyl; lower alkycarbamoyl; amino optionally substituted with lower alkyl, hydroxy(lower)alkyl, acyl, lower alkylsulfonyl and/or phenyl; phenyl optionally substituted with halogen, cyano, phenyl and/or heterocyclyl;
lower alkyl sulfamoyl; cycloalkylsulfamoyl; nitro; alkylenedioxy; phenylazo optionally substituted with lower alkyl; phenoxy; oxo;
heterocyclyl optionally substituted with hydroxy, halogen, lower alkyl, lower alkoxycarbonyl, amino, carbamoyl, phenyl, halogenophenyl, heterocyclyl and/or oxo;
heterocyclyloxy; and/or heterocyclylsulfonyl optionally substituted with lower alkyl
(hereinafter referred to as xe2x80x9c Z is Z-6xe2x80x9d),
a compound wherein Z is optionally substituted phenyl
wherein the substituents is halogen; lower alkyl optionally substituted with halogen, hydroxy, lower alkoxycarbonyl and/or phenyl; lower alkoxy optionally substituted with halogen and/or cycloalkyl; cycloalkyl; cycloalkyloxy; acyl; lower alkylthio; lower alkylcarbamoyl; amino optionally substituted with lower alkyl, hydroxy(lower)alkyl, acyl and/or phenyl; phenyl optionally substituted with piperidyl; cycloalkylsulfamoyl; alkylenedioxy; phenoxy;
morpholinyl or morpholino, each of which is optionally substituted with lower alkyl; piperidyl optionally substituted with hydroxy, lower alkyl, lower alkoxycarbonyl, phenyl, halogenophenyl and/or oxo; pyrrolidinyl optionally substituted with hydroxy, carbamoyl and/or oxo;
piperazinyl optionally substituted with phenyl or pyrimidinyl; dihydropyridyl; pyrrolyl; pyrrolinyl; imidazolyl optionally substituted with halogen and/or lower alkyl; pyrazolyl; thienyl; thiadiazolyl; furyl; oxazolyl; isoxazolyl; tetrazolyl optionally substituted with lower alkyl and/or phenyl; indolinyl; indolyl; tetrahydroquinolyl; benzothiazolyl optionally substituted with lower alkyl; tetrahydroisothiazolyl optionally substituted with oxo; benzopyranyl optionally substituted with oxo; tetrahydropyranyloxy; tetrahydrofuryloxy; morpholinosulfonyl optionally substituted with lower alkyl; and/or piperidylsulfonyl optionally substituted with lower alkyl
(hereinafter referred to as xe2x80x9cZ is Z-7xe2x80x9d),
a compound wherein Z is optionally substituted phenyl
wherein the substituents is halogen, lower alkyl, halogeno(lower)alkyl, lower alkoxy, cycloalkyloxy, lower alkylcarbamoyl, phenyl, lower alkyl morpholino and/or tetrahydropyranyloxy
(hereinafter referred to as xe2x80x9cZ is Z-8xe2x80x9d),
a compound wherein Z is optionally substituted heterocyclyl
wherein the substituents is halogen, hydroxy, lower alkyl, halogeno(lower)alkyl, lower alkoxy, mercapto, lower alkylthio, acyl, carboxy, lower alkoxycarbonyl, amino, lower alkylamino, phenyl, naphthyl, phenylthio optionally substituted with halogen, phenoxy optionally substituted with halogen, oxo, and/or heterocyclyl optionally substituted with lower alkyl
(hereinafter referred to as xe2x80x9cZ is Z-9xe2x80x9d),
a compound wherein Z is thienyl, pyrazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, indazolyl, benzopyranyl, benzoxazolyl, benzothienyl, benzothiazolyl, benzothiazolinyl, benzothiadiazolyl, quinolyl, isoquinolyl, dihydrobenzofuryl, carbazolyl, acridinyl or dibenzofuryl, each of which is optionally substituted with substituents selected from the group of lower alkyl;
halogeno(lower)alkyl; lower alkoxy; lower alkoxycarbonyl; acyl; lower alkoxycarbonyl(lower)alkyl; mercapto; phenyl, naphthyl, phenylthio or phenoxy, each of which is optionally substituted with halogen; furyl; nitro; oxo; and morpholino optionally substituted with lower alkyl) (hereinafter referred to as xe2x80x9cZ is Z-10xe2x80x9d),
a compound wherein Z is thienyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, indolyl, isoindolinyl, benzopyranyl, quinolyl, carbazolyl, dibenzofuryl, benzopyranyl, benzothienyl or benzothiazolyl, each of which is optionally substituted with one or more substituents selected from the group of lower alkyl, halogeno(lower)alkyl, lower alkoxy, lower alkoxycarbonyl, acyl, phenyl, naphthyl, phenylthio, lower alkyl morpholino and oxo) (hereinafter referred to as xe2x80x9cZ is Z-11),
a compound wherein R1 is R1-2, R2 is R2-2, n is 2 and a combination of X, Y and Z, i.e., (X, Y, Z), is any one of the followings.
(X, Y, Z)=(X-3, Y-2, Z-1), (X-3, Y-2, Z-2), (X-3, Y-2, Z-3), (X-3, Y-2, Z-4), (X-3, Y-2, Z-5), (X-3, Y-2, Z-6), (X-3, Y-2, Z-7), (X-3, Y-2, Z-8), (X-3, Y-2, Z-9), (X-3, Y-2, Z-10), (X-3, Y-2, Z-11), (X-3, Y-3, Z-1), (X-3, Y-3, Z-2), (X-3, Y-3, Z-3), (X-3, Y-3, Z-4), (X-3, Y-3, Z-5), (X-3, Y-3, Z-6), (X-3, Y-3, Z-7), (X-3, Y-3, Z-8), (X-3, Y-3, Z-9), (X-3, Y-3, Z-10), (X-3, Y-3, Z-11), (X-4, Y-2, Z-1), (X-4, Y-2, Z-2), (X-4, Y-2, Z-3), (X-4, Y-2, Z-4), (X-4, Y-2, Z-5), (X-4, Y-2, Z-6), (X-4, Y-2, Z-7), (X-4, Y-2, Z-8), (X-4, Y-2, Z-9), (X-4, Y-2, Z-10), (X-4, Y-2, Z-11), (X-4, Y-3, Z-1), (X-4, Y-3, Z-2), (X-4, Y-3, Z-3), (X-4, Y-3, Z-4), (X-4, Y-3, Z-5), (X-4, Y-3, Z-6), (X-4, Y-3, Z-7), (X-4, Y-3, Z-8), (X-4, Y-3, Z-9), (X-4, Y-3, Z-10), (X-4, Y-3, Z-11), (X-5, Y-2, Z-1), (X-5, Y-2, Z-2), (X-5, Y-2, Z-3), (X-5, Y-2, Z-4), (X-5, Y-2, Z-5), (X-5, Y-2, Z-6), (X-5, Y-2, Z-7), (X-5, Y-2, Z-8), (X-5, Y-2, Z-9), (X-5, Y-2, Z-10), (X-5, Y-2, Z-11), (X-5, Y-3, Z-1), (X-5, Y-3, Z-2), (X-5, Y-3, Z-3), (X-5, Y-3, Z-4), (X-5, Y-3, Z-5), (X-5, Y-3, Z-6), (X-5, Y-3, Z-7), (X-5, Y-3, Z-8), (X-5, Y-3, Z-9), (X-5, Y-3, Z-10), (X-5, Y-3, Z-11),
the pharmaceutically acceptable salt, solvate or prodrug thereof.
The NPY Y5 receptor antagonist of the present invention is effective for all of the diseases in which NPY Y5 is involved and it is especially useful for preventing and/or treating obesity and suppressing food intake. Moreover, the antagonist is effective for preventing and/or treating the diseases in which obesity acts as a risk factor, for example, diabetes, hypertension, hyperlipemia, atherosclerosis and acute coronary syndrome.
In addition, the NPY Y5 receptor antagonist of the present invention has a low affinity for NPY Y1 and Y2 receptors, and has a high selectivity for NPY Y5 receptor. NPY causes a sustained vasoconstrictive action in the periphery and this action is mainly via Y1 receptor. Since Y5 receptor is not involved in this action at all, the NPY Y5 receptor antagonist has a low risk of inducing side effects based on the peripheral vasoconstriction, and is expected to be suitably used as a safe medicine.
The NPY Y5 receptor antagonist shows an anti-obestic effect by suppressing food intake. Therefore, it is one of the features that this antagonist does not induce side effects, e.g., an indigestion caused by an anti-obestic agent which inhibits digestion and absorption, and a central side effect such as anti-depression caused by a serotonin transporter inhibitor showing an anti-obesity effect.
A compound of the present invention can be administered orally or parenterally as an anti-obestic agent or anorectic agent. In the case of oral administration, it may be in any usual form such as tablets, granules, powders, capsules, pills, solutions, syrups, buccal tablets and sublingual tablets. When the compound is parenterally administered, any usual form is preferable, for example, injections (e.g., intravenous, intramuscular), suppositories, endermic agents and vapors. Oral administration is particularly preferable because the compounds of the present invention show a high oral absorbability.
A pharmaceutical composition may be manufactured by mixing an effective amount of a compound of the present invention with various pharmaceutical additives suitable for the administration form, such as excipients, binders, moistening agents, disintegrators, lubricants and diluents. When the composition is of an injection, an active ingredient together with a suitable carrier can be sterilized to give a pharmaceutical composition.
Examples of the excipients include lactose, saccharose, glucose, starch, calcium carbonate and crystalline cellulose. Examples of the binders include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin and polyvinylpyrrolidone. Examples of the disintegrators include carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, agar and sodium lauryl sulfate. Examples of the lubricants include talc, magnesium stearate and macrogol. Cacao oil, macrogol, methylcellulose etc. may be used as base materials of suppositories. When the composition is manufactured as solutions, emulsified injections or suspended injections, dissolving accelerators, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents and the like may be added. For oral administration, sweetening agents, flavors and the like may be added.
Although the dosage of a compound of the present invention as an anti-obestic agent or anorectic agent should be determined in consideration of the patient""s age and body weight, the type and degree of diseases, the administration route etc., a usual oral dosage for an adult is 0.05 to 100 mg/kg/day and preferable is 0.1 to 10 mg/kg/day. For parenteral administration, although the dosage highly varies with administration routes, a usual dosage is 0.005 to 10 mg/kg/day, preferably, 0.01 to 1 mg/kg/day. The dosage may be administered in one to several divisions per day.